Chronic gingival inflammation of the soft tissue surrounding the tooth afflicts over half of all American adults. In the most severely affected, progression of this inflammatory process to the deeper periodontal ligaments and alveolar bone results in tooth loss from loss of mandibular anchorage. Gingivitis and periodontitis are initiated by chronic infection of the gingival crevice with bacteria such as Porphryomonas gingivalis. Risk for gingivitis is universal, but subjects with haplotypes of IL-1B producing higher IL-1? levels in crevicular fluid, diabetics and smokers all have a more exuberant response to bacterial biofilm leading to serious periodontal disease. Regular brushing and flossing, and semi-annual scaling and root planing to remove plaque and biofilm are effective preventative strategies in normal individuals, but are inadequate to stop progression of serious periodontal disease in high-risk subjects such as diabetics, in whom interaction of diabetes-related advanced glycation end-products (AGEs) with the receptor for advanced glycation end- products (RAGE) promotes accelerated periodontal inflammation. In Phase I, GlycoMira Therapeutics described a proprietary family of 5 kDa semi-synthetic glycosaminoglycan ethers (SAGEs), derived from sulfation and alkylation of hyaluronic acid (HA), that are intrinsically non-anticoagulant. SAGEs are systemically and topically safe anti-inflammatory agents that block P- and L-selectin, inhibit human neutrophil elastase (HLE), block complement receptor-3 (CR3, also known as Mac-1), and block interaction of RAGE with its known important ligands, including AGEs, high mobility group box-1 protein (HMGB-1) and S100 calgranulins. In Phase I, the GlycoMira team demonstrated that the lead SAGE, GM-0111, has at least five salutary effects for treating periodontitis. First, it decreases IL-1?- and P. gingivalis lipopolysaccharide (LPS)-stimulated IL-1?, prostaglandin E2, and matrix metalloproteinases (MMP) 1, 2, 3, and 9 release from macrophages and human gingival fibroblasts. Second, it blocks CR3-mediated internalization of P. gingivalis by macrophages. Third, it inhibits P. gingivalis LPS-induced formation of multinucleated osteoclasts from blood monocytes. Fourth, it reduces TNF-?, IL-1?, IL-6, and MMP-2 and -9 levels in gingival extracts from diabetic P. gingivalis-infected rats. Finally, and most importantly, it inhibits alveolar bone loss when administered parenterally in a diabetic P. gingivalis-infected rat model of accelerated periodontal disease. In Phase II, GlycoMira will test the hypothesis that GM-0111, can be an effective local therapy for periodontal disease. We propose to (i) use the diabetic rat model to show efficacy of local administration, (ii) explore th ability of GM-0111 to alter or block osteoclast activation and reduce bone resorption, (iii) test tolerability of topical formulations for delivery of GM-0111 into the sulcus in dose-ranging studie in beagle dogs, and (iv) conduct a pivotal study in beagle dogs to test the efficacy of the selected formulation.
Chronic gingival inflammation afflicts over half of all American adults, evolves into frank periodontal disease, and results in tooth loss. Periodontitis is caused by infection of the gingival crevice and production of subgingival microbial plaque, which results in leukocyte-mediated inflammation and alveolar bone resorption. Importantly, periodontal disease is exacerbated by diabetes and smoking, and periodontitis substantially increases the risk of systemic illness such as cardiovascular and renal disease, rheumatoid arthritis, preeclampsia and pre-term delivery. We propose to develop anionic, partially lipophilic hyaluronic acid derivatives as a simple mechanistically-based treatment for this chronic and extraordinarily common dental disorder.
|Savage, Justin R; Pulsipher, Abigail; Rao, Narayanam V et al. (2016) A Modified Glycosaminoglycan, GM-0111, Inhibits Molecular Signaling Involved in Periodontitis. PLoS One 11:e0157310|